Research Article| Volume 38, ISSUE 3, P215-224, June 2005

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Three-dimensional imaging reveals major changes in skin microvasculature in lipoid proteinosis and lichen sclerosus



      Lipoid proteinosis is a rare autosomal recessive disorder characterized by deposition of hyaline-like material in several organs, including skin. Pathogenic mutations have been found in the extracellular matrix protein 1 gene (ECM1). Recent studies have disclosed that ECM1 is also a target antigen for autoantibodies in patients with the acquired disease, lichen sclerosus. Both conditions have been reported to show abnormalities in dermal blood vessels but these changes have not been fully assessed.


      The purpose of this study was to investigate the architecture of the cutaneous microvasculature in lipoid proteinosis and lichen sclerosus to better determine the role of ECM1 in the skin pathology observed in these disorders.


      Labeling of skin biopsies (lipoid proteinosis, lichen sclerosus and control skin) with antibodies to type IV collagen and laminin-1 and reconstruction of the dermal blood vessels using laser confocal microscopy and computer imaging.


      In both lipoid proteinosis and lichen sclerosus there was reduplication of the basement membranes surrounding blood vessel walls. There were enlarged vessels in the mid and deep dermis that were orientated parallel to the dermal-epidermal junction. In addition, the normal capillary loop network in the dermal papillae, as well as the subcutaneous plexus and transverse connecting vessels were lacking in both disorders.


      This study demonstrates that skin microvasculature is grossly altered when ECM1 is targeted by inherited mutations (lipoid proteinosis) or acquired autoantibodies (lichen sclerosus) and that this glycoprotein appears to have an important role in regulating blood vessel physiology and anatomy in the skin.


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        • Urbach E.
        • Wiethe C.
        Lipoidosis cutis et mucosae.
        Virchows Arch Pathol Anat Phisiol. 1929; 273: 285-319
        • Muda A.O.
        • Paradisi M.
        • Angelo C.
        • Mostaccioli S.
        • Atzori F.
        • Puddu P.
        • Faraggiana T.
        Lipoid proteinosis: clinical, histologic, and ultrastructural investigations.
        Cutis. 1995; 56: 220-224
        • Cohen A.D.
        • Vardy D.A.
        • Cagnano E.
        • Zvulunov A.
        • Naimer S.A.
        A 17-year-old adolescent with acneiform skin changes. Diagnosis: lipoid proteinosis (Urbach-Wiethe disease, Hyalinosis Cutis et Mucosae).
        Eur J Pediatr. 1999; 158: 863-864
        • Oz F.
        • Kalekoglu N.
        • Karakullukcu B.
        • Ozturk O.
        • Oz B.
        Lipoid proteinosis of the larynx.
        J Laryngol Otol. 2002; 116: 736-739
        • Caccamo D.
        • Jaen A.
        • Telenta M.
        • Varela E.
        • Tiscornia O.
        Lipoid proteinosis of the small bowel.
        Arch Pathol Lab Med. 1994; 118: 572-574
        • Friedman L.
        • Mathews R.D.
        • Swanepoel P.D.
        Radiographic and computed tomographic findings in lipid proteinosis. A case report.
        S Afr Med J. 1984; 65: 734-735
        • Kleinert R.
        • Cervos-Navarro J.
        • Kleinert G.
        • Walter G.F.
        • Steiner H.
        Predominantly cerebral manifestation in Urbach–Wiethe's syndrome (lipoid proteinosis cutis et mucosae): a clinical and pathomorphological study.
        Clin Neuropathol. 1987; 6: 43-45
        • Hamada T.
        Lipoid proteinosis.
        Clin Exp Dermatol. 2002; 27: 624-629
        • Olsen D.R.
        • Chu M.L.
        • Uitto J.
        Expression of basement membrane zone genes coding for type IV procollagen and laminin by human skin fibroblasts in vitro: elevated alpha 1 (IV) collagen mRNA levels in lipoid proteinosis.
        J Invest Dermatol. 1988; 90: 734-738
        • Navarro C.
        • Fachal C.
        • Rodriguez C.
        • Padro L.
        • Dominguez C.
        Lipoid proteinosis. A biochemical and ultrastructural investigation of two new cases.
        Br J Dermatol. 1999; 141: 326-331
        • Fleischmajer R.
        • Kieg T.
        • Dziadek M.
        • et al.
        Ultrastructure and composition of connective tissue in hyalinosis cutis et mucosae skin.
        J Invest Dermatol. 1984; 82: 252-258
        • Moy L.S.
        • Moy R.L.
        • Matsuoka L.Y.
        • Ohta A.
        • Uitto J.
        Lipoid proteinosis: ultrastructural and biochemical studies.
        J Am Acad Dermatol. 1987; 16: 1193-1201
        • Hausser I.
        • Biltz S.
        • Rauterberg E.
        • Frosch P.J.
        • Anton-Lamprecht I.
        Hyalinosis cutis et mucosae (Urbach–Wiethe disease)-ultrastructural and immunological characteristics.
        Hautarzt. 1991; 42: 28-33
        • Hamada T.
        • McLean W.H.
        • Ramsay M.
        • et al.
        Lipoid proteinosis maps to 1q21 and is caused by mutations in the extracellular matrix protein 1 gene (ECM1).
        Hum Mol Genet. 2002; 11: 833-840
        • Hamada T.
        • Wessagowit V.
        • South A.P.
        • et al.
        Extracellular matrix protein 1 gene (ECM1) mutations in lipoid proteinosis and genotype-phenotype correlation.
        J Invest Dermatol. 2003; 120: 345-350
        • Chan I.
        • El-Zurghany A.
        • Zendah B.
        • Benghazil M.
        • Oyama N.
        • Hamada T.
        • McGrath J.A.
        Molecular basis of lipoid proteinosis in a Libyan family.
        Clin Exp Dermatol. 2003; 28: 545-548
        • Mathieu E.
        • Meheus L.
        • Raymackers J.
        • et al.
        Characterization of the stromal osteogenic cell line MN7: identification of secreted MN7 proteins using two-dimensional polyacrylamide gel electrophoresis, western blotting and microsequencing.
        J Bone Miner Res. 1994; 9: 903-913
        • Smits P.
        • Ni J.
        • Feng P.
        • Wauters J.
        • et al.
        The human extracellular matrix gene 1 (ECM1): genomic structure, cDNA cloning, expression pattern and chromosomal localization.
        Genomics. 1997; 45: 487-495
        • Johnson M.R.
        • Wilkin D.J.
        • Vos H.L.
        • et al.
        Characterization of the human extracellular matrix protein 1 gene on chromosome 1q21.
        Matrix Biol. 1997; 16: 289-292
        • Deckers M.M.
        • Smits P.
        • Karperien M.
        • et al.
        Recombinant extracellular matrix protein 1 inhibits alkaline phosphatase activity and mineralization of mouse embryonic metatarsals in vitro.
        Bone. 2001; 28: 14-20
        • Han Z.
        • Ni J.
        • Smits P.
        • et al.
        Extracellular matrix protein 1 (ECM1) has angiogenic properties and is expressed by breast tumor cells.
        FASEB J. 2001; 15: 988-994
        • Oyama N.
        • Chan I.
        • Neill S.M.
        • et al.
        Autoantibodies to extracellular matrix protein 1 in lichen sclerosus.
        Lancet. 2003; 362: 118-123
      1. Kowalewski C, Kozłowska A, Zawadzka M, et al. Alterations of basement membrane zone and cutaneous microvasculature in morphea and extragenital lichen sclerosus. J Am Dermatopathol, in press.

        • Kowalewski C.
        • Kozłowska A.
        • Zawadzka M.
        • Woźniak K.
        • et al.
        Alterations of basement membrane zone in bullous and non-bullous variants of extragenital lichen sclerosus.
        J Am Dermatopathol. 2004; 26: 96-101
        • Braverman I.M.
        The cutaneous microcirculation.
        J Invest Dermatol Symp Proc. 2000; 5: 3-9
        • Chan I.
        The role of extracellular matrix protein 1 in human skin.
        Clin Exp Dermatol. 2004; 29: 52-56
        • Mongiat M.
        • Fu J.
        • Oldershaw R.
        • Greenhalgh R.
        • Gown A.M.
        • Iozzo R.V.J.
        Perlecan protein core interacts with extracellular matrix protein 1 (ECM1), a glycoprotein involved in bone formation and angiogenesis.
        Biol Chem. 2003; 278: 17491-17499
        • Terlizzi J.
        • Li K.
        • Aho S.
        • et al.
        Characterization of ECM-1 protein interactions by yeast two-hybrid system.
        J Invest Dermatol. 2004; 122: A38
        • Ponce M.L.
        • Kleinman H.K.
        Identification of redundant angiogenic sites in laminin alpha1 and gamma1 chains.
        Exp Cell Res. 2003; 285: 189-195
        • Henry M.D.
        • Satz J.S.
        • Brakebusch C.
        • Costell M.
        • Gustafsson E.
        • Fassler R.
        • Campbell K.P.
        Distinct roles for dystroglycan, beta1 integrin and perlecan in cell surface laminin organization.
        J Cell Sci. 2001; 114: 1137-1144
        • McNiff J.M.
        • Glusac E.J.
        • Lazova R.Z.
        • Carroll
        Morphea limited to the superficial reticular dermis: an underrecognized histologic phenomenon.
        Am J Dermatopathol. 1999; 21: 315-319